1. Field of the Invention
This invention relates generally to macromolecular contrast agents used in diagnostic imaging, and methods of synthesizing, using and degrading such compounds.
2. Description of the Related Art
Magnetic resonance imaging (MRI) is a non-invasive method for medical diagnosis. Paramagnetic metal complexes are often used as contrast agents to enhance the image contrast between normal tissue and diseased tissue. Paramagnetic metal ions that are typically used in diagnostic procedures include manganese (Mn2+), iron (Fe+3), and gadolinium (Gd+3). Chelates of Gd+3 are frequently used as MRI contrast agents because of their long electronic relaxation time and high magnetic moment. Gadolinium-based contrast agents include small molecular gadolinium complexes such as Gd(III)(DTPA) [diethylenetriaminepentaacetate] and Gd(III)(DOTA) [1,4,7,10-tetraazadodecanetetraacetic acid], and their derivatives. Use of stable, non-toxic paramagnetic chelates in conjunction with various diagnostic procedures, such as MRI, have been used in the prior art to increase the accuracy of diagnosis.
Macromolecular MRI contrast agents, sometimes referred to as long-circulating or blood pool agents, are particularly useful because of their prolonged retention time in the blood pool. These agents typically increase the magnetic resonance signal of blood by shortening the T1 relaxation time of blood and can be used for a variety of diagnostic procedures, including magnetic resonance angiography. Because of the enhanced permeability and retention, these contrast agents accumulate effectively in solid tumors and have a potential in contrast enhancement in MR cancer imaging. However, the macromolecular contrast agents currently available to the medical community have poor clearance rates. As a result of poor clearance rates, use of Gd macromolecular agents may result in Gd accumulation in bone and other tissues, resulting in toxicity and adverse side-effects.